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Published on: September 13, 2022
Dynamic profiling of medulloblastoma surfaceome
David Bakhshinyan1,2, Yujin Suk1,2,3, Laura Kuhlmann4
1McMaster Centre for Discovery in Cancer Research, McMaster University, MDCL 5027, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
Abstract:
Medulloblastoma (MB) is the most common type of malignant pediatric brain cancer. The current standard of care (SOC) involves maximal safe resection and chemoradiotherapy in individuals older than 3 years, often leading to devastating neurocognitive and developmental deficits. Out of the four distinct molecular subgroups, Group 3 and 4 have the poorest patient outcomes due to the aggressive nature of the tumor and propensity to metastasize and recur post therapy. The toxicity of the SOC and lack of response in specific subtypes to the SOC underscores the urgent need for developing and translating novel treatment options including immunotherapies. To identify differentially enriched surface proteins that could be evaluated for potential future immunotherapeutic interventions, we leveraged N-glycocapture surfaceome profiling on Group 3 MB cells from primary tumor, through therapy, to recurrence using our established therapy-adapted patient derived xenograft model. Integrin 𝛼5 (ITGA5) was one of the most differentially enriched targets found at recurrence when compared to engraftment and untreated timepoints. In addition to being enriched at recurrence, shRNA-mediated knockdown and small molecule inhibition of ITGA5 have resulted in marked decrease in proliferation and self-renewal in vitro and demonstrated a survival advantage in vivo. Together, our data highlights the value of dynamic profiling of cells as they evolve through therapy and the identification of ITGA5 as a promising therapeutic target for recurrent Group 3 MB.
Insights
Researchers identified Integrin α5 (ITGA5) as a promising target for recurrent Group 3 medulloblastoma (MB). Targeting ITGA5 reduced tumor growth and improved survival, offering hope for novel immunotherapies against this aggressive pediatric brain cancer.
Area of Science:
- Oncology
- Neuro-oncology
- Cancer Biology
Background:
- Medulloblastoma (MB) is the most common malignant pediatric brain tumor.
- Current standard of care (SOC) for MB, involving surgery and chemoradiotherapy, causes significant neurocognitive deficits.
- Group 3 and 4 MB subtypes exhibit poor outcomes due to aggressive behavior and recurrence.
- Novel therapeutic strategies, including immunotherapies, are urgently needed for MB, especially for recurrent or refractory cases.
Purpose of the Study:
- To identify differentially enriched surface proteins for potential immunotherapeutic targets in Group 3 medulloblastoma.
- To dynamically profile surfaceome changes in Group 3 MB cells throughout therapy and recurrence.
- To evaluate the therapeutic potential of identified targets in preclinical models.
Main Methods:
- N-glycocapture surfaceome profiling was employed on a patient-derived xenograft model of Group 3 MB.
- Cells were analyzed at different stages: primary tumor, during therapy, and at recurrence.
- Functional studies included shRNA-mediated knockdown and small molecule inhibition of target proteins.
- In vitro proliferation and self-renewal assays, along with in vivo survival studies, were performed.
Main Results:
- Integrin α5 (ITGA5) was identified as a significantly enriched surface protein at recurrence compared to earlier timepoints.
- Knockdown or inhibition of ITGA5 led to a substantial decrease in Group 3 MB cell proliferation and self-renewal in vitro.
- Targeting ITGA5 demonstrated a significant survival advantage in vivo.
- Dynamic surfaceome profiling revealed therapeutic vulnerabilities that emerge during tumor evolution.
Conclusions:
- Integrin α5 (ITGA5) is a promising therapeutic target for recurrent Group 3 medulloblastoma.
- Targeting ITGA5 may offer a novel treatment strategy to overcome SOC limitations and improve outcomes.
- Dynamic profiling of tumor evolution is crucial for identifying effective therapeutic targets.
